RNAi Firms Find a New Rival (and Partner) in an Old Technology

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What? Can antisense possibly be hot again? Many people wondered if the decades-old RNA-targeting approach to drug development was even still alive. But look again. Recent events show antisense isn’t just hanging in there; its products might actually beat their much-ballyhooed RNAi-based rivals (from the likes of firms like Cambridge’s Alnylam Pharmaceuticals and Worcester’s RXi Pharmaceuticals) to market.

Carlsbad, CA’s Isis Pharmaceuticals (NASDAQ: ISIS) has had a recent string of deals that suggests second-generation antisense really does have legs. What’s more, because of the antisense pioneer’s huge patent estate, companies will likely need to cut a deal with Isis to work in RNA targeting of any kind–including in the budding new field of microRNA-based drug development. (Alnylam, for instance, has a longstanding strategic alliance with Isis, and last month the two announced a joint venture focused on microRNA.) Meanwhile, Alnylam (NASDAQ: ALNY) is weathering controversy over safety concerns. In the wake of all this, RNAi companies could end up watching underdog Isis, with its “passé” antisense drugs, finish ahead in one of the pharmaceutical industry’s most exciting races.

Antisense and RNAi companies are all trying to do the same thing—create a new class of drugs that whack disease-causing RNA. Messenger RNA (mRNA) is the middle man in the genes-to-protein process. Most drugs attack the bad proteins themselves. Instead, antisense and RNAi companies try to stop “bad” proteins from even being made. Antisense uses single stranded DNA while the RNAi folks typically use some kind of small double stranded or looped RNA. The differences used to be clearer, but nowadays you hear about all kinds of approaches, including hybrids—hence the patent minefield. The big difference is that RNAi is a natural process that the cell itself uses to turn genes off.

Oh, and RNAi is very new while antisense has been around forever. A number of high-profile antisense compounds have already tanked gloriously on the way to market. Only one has been approved after 20 years of trying, and that lone drug is a niche ocular therapy from Isis—it’s more of an aside than a breakthrough. So, when RNAi came along a few years ago it was a classic Cinderella story with antisense relegated to the part of ugly stepsister. Suddenly, here was RNAi—a simple, very powerful way to knock out mRNA that seemed like it would lead especially quickly to marketable drugs. Antisense companies, including Isis and Cambridge, MA-based Hybridon (now Idera Pharmaceuticals), were shoved aside as yesterday’s technology.

But things are changing.

For one thing, the tough questions are now popping up for RNAi. Last year, a bunch of mice died in a key study by Stanford researcher Mark Kay. In the resulting Nature paper, Kay suggested that when you harness the cell’s innate RNAi pathway, natural production of microRNAs might inadvertently be curbed. That’s troubling. Although microRNAs have only recently emerged as big players in cellular biology, it is increasingly clear that they are very important. Alnylam responded last week with its own Nature paper and a press release. David Burncroft, one of that study’s authors, said via e-mail that it shows “Our approach to RNAi using siRNA molecules does not interfere with microRNA synthesis and function in the liver.”

Kay is not sure the latest paper settles the safety question, but he applauds it for “adding to the promise of RNAi therapeutics.” John Rossi from Southern California’s City of Hope concurs. “They have a good claim that they aren’t triggering toxicity,” he says. “But they haven’t proved it doesn’t happen [with these types of molecules].”

Also, having started so much later, (the first RNAi therapeutic firms were founded around 2002 and 2003) RNAi companies are way behind antisense firms in building their pipelines, and they don’t seem to be catching up that quickly. Only one of Alnylam’s drugs is in clinical trials yet—a respiratory syncytial virus treatment in Phase II, which the company says it will report on in the second half of this year.

Meanwhile, antisense suddenly has newfound momentum. Just a couple years ago, Isis CEO Stanley Crooke was a tortured man. The company had gotten that one little approval and then experienced a brutal string of failures. Isis’s new thing was second-generation antisense based on a novel chemistry. Unfortunately, all those new drugs were still creeping along the near end of the product pipeline.

Crooke was adamant that they were still in the game. “We’ve got the patents, we’ve got the patents!” he kept saying during one conversation. Just hearing the word “RNAi” launched him into a long winded, but well reasoned, explanation about how people who differentiated RNAi from antisense were really just muddying the waters: Isis’s years of research and huge patent portfolio, he said, put them in the ideal position to capitalize on RNA interference or any other form of RNA-targeting, and the newcomers were just trying to jump on their bandwagon.

At the time, it was difficult to know whether, like Tolkien’s Gollum, he was indeed cradling a treasure much more valuable than most people realized, or if he was just trying to keep Isis alive by any means. Now, the answer seems clear.

“The sea change,” as Crooke calls it, started in early May, when Isis netted a collaboration with Bristol-Myers Squibb around a new anti-cholesterol target. A few months later, a string of deals ensued starting with an announcement on September 7 that Isis and Alnylam were launching Regulus Therapeutics, a joint venture around microRNA-based drugs.

This is one of the most exciting and burgeoning new fields in medicine. No less a luminary than David Baltimore joined Regulus’ board of directors and became chair of the new company’s scientific advisory board. Regulus uses IP from both companies, but, “The only real way to target a microRNA is antisense,” says Crooke.

Just a few days after Regulus’s founding was announced, Isis inked a metabolic-disease deal with Ortho-McNeil worth potentially up to $230 million. That deal covers several compounds, two of which were held by Symphony GenIsis up until last week, when Isis re-acquired the firm, which it has spun off in 2006 expressly to keep its metabolic program alive.

Isis will be reporting Phase II data on one of those four drug candidates next Monday. Crooke won’t be fully vindicated until one of those second-generation molecules finally crosses the finish line. And good news for antisense could ultimately be good news for RNAi companies. “Any progress in the field of RNA-based therapeutics would be progress for the industry,” says Alnylam COO Barry Greene.

During that conversation two years ago, a weary Crooke said “The two most difficult things are raising children and drug discovery.” Hopefully his children have handed him fewer challenges than the antisense has. Meanwhile, the question for RNAi-based companies is: How quickly can a toddler turn into a teen? How’s that for a really scary question?

A note of encouragement to Mr. Crooke: the speed and success rate at which toddlers turn into teens is greatly determined by the intelligence, stamina and patience of the parents. He obviously possesses all of these,and his endeavors will do very well. It is truly a “brave new world.” Best wishes to Isis, which I believe has a bright new future!